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Disease and treatment

Hunger hormone counteracts Huntington’s disease

The stomach produces a hormone called ghrelin when we are hungry. Now new research shows that ghrelin can counteract some of the symptoms of Huntington’s disease, which is a disabling neurological disease.

In 2001, researchers discovered ghrelin, a hormone the stomach secretes when we are hungry. Since then, researchers have been studying ghrelin to determine whether blocking its secretion can curb obesity.

Researchers from the University of Copenhagen, however, have examined ghrelin in a completely different context, and their research now shows that it can potentially be useful in counteracting Huntington’s disease, which is severely disabling.

In a new study, the researchers showed that ghrelin can delay the symptoms of Huntington’s disease in mice. If this result can be replicated among humans, a new treatment may be in the pipeline for people with the disease who have no other pharmaceutical treatment options.

”Naturally, it is difficult to predict what will emerge from this, but I think that ghrelin may have the potential to give people with Huntington’s disease several more years with higher quality of life,” says the researcher behind the new study, Birgitte Holst, Professor with Special Responsibilities, Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

The new study was recently published in the Journal of Neuroendocrinology.

Huntington’s affects the whole body

Huntington’s disease is a dominantly inherited disorder that often develops later in life. It can suddenly develop at 30 years or even 50 years, and the person often has a spouse and children when the disease erupts.

The disease is neurodegenerative and manifests itself by incipient problems with movement, changes in personality, declining intellect and weight loss.

People with Huntington’s also often develop depression, and their circadian rhythms become disturbed so they are awake and asleep at arbitrary times of the day and night.

Life expectancy following diagnosis is often only 15–20 years.

“In Huntington's disease, specific neurons become degraded and cause the symptoms. In our trials, we tested ghrelin to treat the disease, since we know that ghrelin protects the brain, reducing depression, and it also helps to develop fatty tissue. This means that it basically counteracts two important aspects of disease development,” explains Birgitte Holst.

Delaying symptoms

In their experiments, the researchers from the University of Copenhagen used mice that had been genetically engineered to have Huntington’s disease. The genetic cause is too many copies of some of the building blocks of DNA.

These mice express all the classic signs of the disease: they lose both fatty tissue and muscle mass, are stressed and confused, sleep poorly at night etc.

The researchers divided the mice with presymptomatic Huntington’s into two groups and gave one group ghrelin and the other a placebo. The researchers then examined how the disease developed among the mice in the two groups.

The experiment showed that the mice responded positively to the treatment with ghrelin. The mice that received the hormone did not lose as much muscle mass or fatty tissue as the control mice, and their circadian rhythm also remained normal for longer.

Thus, ghrelin cannot prevent Huntington’s disease from developing but may provide a novel therapeutic option for delaying disease progression.

”It was very positive that the mice responded so well to the treatment, which normalized their eating patterns and helped them to not lose fat and muscle mass to the same extent. In addition, we assume that the mice’s cognitive function improves when they have a more normal circadian rhythm,” says Birgitte Holst.

People may also benefit

The study is only based on a mice model, and more research is required to conclude whether ghrelin can also affect people with Huntington’s disease.

Nevertheless, Birgitte Holst is optimistic.

Her research group has now begun to contact neurologists who treat people with Huntington’s disease to hear what they think about the potential of using ghrelin.

The researchers will proceed with clinical trials after talking to doctors and research colleagues and assessing the potential of ghrelin.

However, ghrelin will probably never cure the disease. Instead, it can potentially be used to give people several good years without symptoms, similar to some types of cancer treatment that also only prolong life.

Treating people in the early stages of the disease

Birgitte Holst emphasizes that ghrelin currently appears to have the potential to function best for people with the earliest symptoms of Huntington’s disease. Ideally, treatment should be initiated at the first signs of disease.

However, this requires knowing that a person has Huntington’s disease before the symptoms emerge.

However, this can often be detected because Huntington’s disease is dominantly inherited, which means that if a mother or father has it, their children have a 50% chance of developing it.

”It would be really interesting to find a group of people who have Huntington’s disease but with no signs and start treating them with ghrelin before the symptoms emerge. We could determine whether ghrelin also works on people, potentially prolonging the good years of their lives,” concludes Birgitte Holst.

Ghrelin-mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington’s disease” has been published in the Journal of Neuroendocrinology. The Novo Nordisk Foundation awarded a grant in 2014 to Birgitte Holst for the project In Vivo Characterization of Ghrelin Receptor–Mediated Signaling in the Hypothalamus Using Biased Ligand and KO Models and a grant in 2018 for the project The Endogenous Ghrelin Receptor Antagonist Leap2 as the Basis for a Novel Anti-obesity Drug.

Birgitte Holst
Professor, external
The common research theme of the Molecular Pharmacology Laboratory is the relationship between structure and function of 7TM (seven transmembrane segment), G protein-coupled receptors. The structure-function relationship is studied in close collaboration with computational chemistry groups – in particular Professor Thomas Frimurer and his group – and various medicinal chemistry groups in academia and in the biotech and pharmaceutical industry. Pharmacological concepts from the invtro studies are carried over into the in vivo pharmacological setting and probed in various animal models.